Receptors
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CONTENTS
• Introduction - receptor
• Drug – receptor interactions
• Cell surface receptors
• Intracellular receptors
• Comparison of receptor types
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RECEPTOR?
Specialized areas of cell to which drugs get
bound.
They are regulatory protein macro molecules
Drug should have –selectivity to a receptor ;
receptor should have - ligand specificity to
elicit action.
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D r u g R e c e p t o r I n t e ra c ti o n s
Effect of drug is attributed to two factors
Affinity : tendency of the drug to bind to receptor
and form D-R complex .
Efficacy or intrinsic activity : ability of the drug to
trigger pharmacological responses after forming D-R
complex .
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CONTD…
Based on affinity and intrinsic activity :
Full agonist : high affinity
high intrinsic activity
Eg. Methacholine on acetylcholine receptors
Antagonist : only affinity
no intrinsic activity Eg. Atropine on
muscarinic receptors
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CONTD..
Partialagonist: full affinity
intrinsic activity low
Eg. Naloxene on opioid receptors
saralasin on angiotensin receptors
Inverse
agonist: full affinity
intrinsic activity
Eg. Beta carbolines on
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BZP receptor.
CLASSIFICATION -
Cell surface Intracellular
1. Inotropic 1. Nuclear receptors
3. Metabotropic
5. Ligand regulated
trans membrane
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A. Cell surface receptor
1. G- Protein Coupled Receptor (GPCR )
• metabotropic or 7-transmembrane
spanning (heptahelical) receptors.
• coupled to intracellular effector systems
via a G-protein, GPCR.
mAChRs, adrenoceptors, DA, 5-HT,
opiate, peptide, purinoceptors,
orphans etc 11
STRUCTURE
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-ROLE
• Membrane resident proteins – recognize activated
GPCRs- pass message to effector system.
• Occurs in interaction with guanine nucleotides ;
freely moving in cytoplasm.
• α, β and γ subunits – trimer in resting state.
• The 3 subunits are attached to GPCR through fatty
acid chain – reaction called prenylation.
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SUBTYPES
G-PROTEIN RECEPTOR FOR SIGNALLING
PATHWAY
GS Beta adrenergic Adenylyl cyclase
amines, glucagon
histamine, serotonin CAMP
•Excitatory effects
Gi1, Gi2, Gi3 Alpha2 adrenergic adenylyl cyclase
amines, mAchR, CAMP
opioid, Cardiac K+
serotonin channel open-
hear
Golf Olfactory epithelium t ratecyclase
Adenylyl
–CAMP
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G- RECEPTOR SIGNALLING
PROTEIN FOR PATHWAY
GO NT ,Opioid Not
cannabinoid clear
Gq mAchR, PLC
serotonin IP3 , DAG
5HT1C Cytoplasmic Ca
Gt1 , Gt2 Rhodopsin
and cGMP
colour phosphodiesteras
opsins in
retinal rod and cGMP
cone cells
e- 18
Systems involved in s i g n a l t r a n sd uc t i o n
The adenyly cyclase / cAMP system
The Phospholipase C / inositol phosphate system
The Ion channels
The Rho A /Rho kinase system
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Adenylyl Cyclase/ cAMP System
c AMP –nucleotide synthesized from ATP - by adenylyl cyclase,
metabolized by PDE.
Regulate enzymes of metabolism, growth, contractile
proteins of muscle.
NT - acts on GPCR –Gs/Gi activated –produce effects– by inc
or dec. activity of adenylyl cylase-and cAMP.
c AMP- activate - Protein kinases-activate/inactivate enzymes
by phosphorylation – cellular events.
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P ho s ph o l i p a s e C - Inositol System
• Phospholipase C : Cleaves membrane
phospholipids - phosphoinositides.
• PLC beta – cleaves phosphatidylinositol (4,5)
bis Phosphate PIP2 into DAG and IP3.
• DAG and IP3- Secondary messengers – elicit
cellular responses.
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ION CHANNELS
GPCR- directly control ion channel-without secondary
messenger. Eg. mAchR in heart – activate K+ channel.
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SYSTEM
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2. ENZYME LINKED RECEPTORS
Involved in growth, proliferation, differentiation or
survival-called growth factors.
Mediate actions of protein mediators- GF,
cytokines , harmones- insulin and leptin.
Slow – require the expression of new genes.
Single membrane spanning helix - extracellular
ligand binding domain - intracellular domain.
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Structure of Kinases linked
receptors
Extracellular domain
Binds to the ligand (growth factor)
Trans membrane domain
Y
Y
Intracellular domain
Y
Endogenous kinases bind
and get phosphorlated
Y
Y
Y 28
TYPES
Receptor Tyrosine Kinases (RTK)
Eg. EGF , NGF , insulin receptor
Serine/ threonine kinases Eg. TGF
Cytokine receptors Eg.
Cytokines , CSF
Guanylyl cyclase receptors Eg. ANP
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Gene Kinase cascade
transcription
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Important pathways activated :
1.The Ras/Raf/mitogen- activated protein (MAP)
kinase pathway
activated by tyrosine kinases.
important in cell division, growth,
differentiation.
2. The JAK/STAT pathway
- activated by cytokines.
- controls synthesis and release of
inflammatory mediators. 31
3. Ion Channel Linked Receptors
• Also called ionotropic receptors.
• involved mainly in fast synaptic transmission.
Eg: nAchR, GABAA, and glutamate receptors of
the NMDA, AMPA and kainate types.
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Characteristi cs of ion channels
• Protein molecules form water filled pores
that span the membrane.
• Switch between open and closed states.
• Rate and Direction of movement depends on
electrochemical gradient of the ions
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Structure
• Ligand binding site in extracellular domain.
4 subunits α, β, γ and δ.
α2, β, γ - pentameric str - 2 ligand binding
sites
• Each subunit spans the membrane 4 times; all
subunits form a central pore.
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Ligand binding
site
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GATING MECHANISM IN GABA A
RECEPTOR
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Due to the concentration changes of different ions the
following effects are seen.
Increase in Na and Ca levels- excitatory
Decrease in Na and Ca levels- inhibitory
Increase in K levels – inhibitory
Decrease in K levels – excitatory
Increase in Cl levels – inhibitory
Decrease in Cl levels- excitatory
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IMPORTANCE
Generation , propagation of nerve impulse.
Synaptic transmission of neurons.
Muscle contraction.
Salt balance.
Hormone release.
Muscle relaxants , anti-arrhythmatics, anesthetics –
act by blocking ion channels.
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B. Intracellular Receptors
Ligand activated transcription factors.
Present in soluble form – either in cytoplasm or
nucleus – freely diffusible.
Transduce signals by- modifying gene transcription.
Eg: steroid hormones, thyroid hormones, vit D and A,
orphan receptors
Play vital role in endocrine signaling and metabolic
regulation.
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Summary
Extensive research done on Receptor pharmacology
lead to discovery of new drug targets for
treatment of several diseases.
Still requires discovery of new receptor types and the
mechanisms of many orphan receptors that can result
in effective treatment of many diseases.
Requires development of receptor crystallization
etc.
Much to be discovered about the nuclear receptors. 44
